TIMM29在乙型肝炎病毒生命周期中的功能作用分析

IF 1.9 4区 医学 Q4 IMMUNOLOGY
Limia Abueldahab, Yadarat Suwanmanee, Nelly Muriungi, Eriko Ohsaki, Masami Wada, Shihoko Kimura-Ohba, Keiji Ueda
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引用次数: 0

摘要

乙型肝炎病毒(HBV)引起慢性乙型肝炎,可发展为肝硬化和肝细胞癌。HBV与各种细胞器和蛋白质有复杂的相互作用,确保有效的子代病毒产生。我们之前报道了一种线粒体蛋白TIMM29通过与HBV preS1蛋白的相互作用来调节HBV的生命周期。在这里,我们使用timm29敲除的HB611 (TIMM29KO/HB611)细胞(一种基于Huh6细胞稳定产生hbv的细胞系)建立了表达Halo-TIMM29wt-、Halo-TIMM29:∆99-192-和Halo-TIMM29:92-194的细胞。我们发现HBV抗原的表达和复制在稳定表达全长TIMM29的细胞中下调,而在表达TIMM29缺失突变体的细胞中则不下调。另一方面,在TIMM29敲除C4 (TIMM29KO/C4)的情况下,除了全长TIMM29 (Halo-TIMM29wt)表达细胞外,这些现象没有重现,TIMM29敲除C4 (TIMM29KO/C4)是一种表达人ntcp的HepG2细胞系,能够感染和扩增HBV。通过基因表达芯片,我们发现了TIMM29KO/HB611和TIMM29KO/C4中ARRDC3和BASP1的下调。研究表明,定位于线粒体内膜的TIMM29作为一个信号中枢,协调激活ARRDC3和BASP1的表达来限制HBV转录。TIMM29突变体在TIMM29KO/HB611和TIMM29KO/C4细胞中的表达表明,ARRDC3依赖于TIMM29的HBV pres1结合区(氨基酸99-189)。相反,BASP1的表达随细胞类型的不同而变化,表明有其他的调控机制。因此,这项研究将显著促进我们对timm29介导的HBV扩增抑制的理解,并导致针对HBV的抗病毒策略和治疗干预的改进。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Analysis of the Functional Role of TIMM29 in the Hepatitis B Virus Life Cycle

Analysis of the Functional Role of TIMM29 in the Hepatitis B Virus Life Cycle

Hepatitis B virus (HBV) causes chronic hepatitis B, which can progress to liver cirrhosis and hepatocellular carcinoma. HBV has complex interactions with various cell organelles and proteins that ensure effective progeny virus production. We previously reported that a mitochondrial protein, TIMM29, should regulate the HBV life cycle through interactions with the HBV preS1 protein. Here, we established Halo-TIMM29wt-, Halo-TIMM29:∆99–192-, and Halo-TIMM29:92–194-expressing cells using TIMM29-knockout HB611 (TIMM29KO/HB611) cells, a stably HBV-producing cell line based on Huh6 cells. We found that HBV antigen expression and replication were downregulated in cells stably expressing full-length TIMM29, but not in those expressing TIMM29 deletion mutants. On the other hand, in the case of TIMM29-knockout C4 (TIMM29KO/C4), which is a human NTCP-expressing HepG2 cell line that is competent for HBV infection and amplification, these phenomena were not reproduced, except in full-length TIMM29 (Halo-TIMM29wt)-expressing cells. Using gene expression microarrays, we identified downregulation of ARRDC3 and BASP1 in TIMM29KO/HB611 and TIMM29KO/C4. It was suggested that TIMM29 localized at the mitochondrial inner membrane served as a signaling hub, orchestrating the activation of ARRDC3 and BASP1 expression to restrict HBV transcription. The expression of TIMM29 mutants in TIMM29KO/HB611 and TIMM29KO/C4 cells suggested that ARRDC3 was dependent on the HBV preS1-binding region of TIMM29 (amino acids 99–189). In contrast, BASP1 expression varied according to cell type, indicating additional regulatory mechanisms. Thus, this study should significantly advance our understanding of TIMM29-mediated inhibition of HBV amplification and lead to improvements in antiviral strategies and therapeutic interventions against HBV.

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来源期刊
Microbiology and Immunology
Microbiology and Immunology 医学-免疫学
CiteScore
5.20
自引率
3.80%
发文量
78
审稿时长
1 months
期刊介绍: Microbiology and Immunology is published in association with Japanese Society for Bacteriology, Japanese Society for Virology, and Japanese Society for Host Defense Research. It is peer-reviewed publication that provides insight into the study of microbes and the host immune, biological and physiological responses. Fields covered by Microbiology and Immunology include:Bacteriology|Virology|Immunology|pathogenic infections in human, animals and plants|pathogenicity and virulence factors such as microbial toxins and cell-surface components|factors involved in host defense, inflammation, development of vaccines|antimicrobial agents and drug resistance of microbes|genomics and proteomics.
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